The Role of Sensory Protein Kinases in the Metabolic Regulation of Cancer Cells
Julianne H. Grose
Metabolic Disease:
An Increasing Health Crisis
Dec 11th, 2003
The Economist
Resource
Resource Allocation:
Allocation: the
the Intracellular
Intracellular Fates
Fates of
of Glucose
Glucose
glucose
membrane structural
components
(glucans, etc)
glucose-1-P
storage
(glycogen, etc)
glucose-6-P
(NADH, ATP,
vitamins, etc. )
protein glycosylation
fats
Glycolysis
UDP-glc
pyruvate
Pentose Phosphate
Pathway
(NADPH, vitamins,
nucleotides, etc)
acetaldehyde
NAD+
fermentation
(NADH, ATP,
vitamins, amino acids) TCA
ATP respiration
ethanol
Protein Kinases Regulate Cellular Processes Through Phosphorylation
ATP
ADP
Protein
Protein
P
Protein Kinases
Enzymatic Activity
Cellular Localization
Binding Partners
Stability/degradation
Human Protein Kinase Overview
Nutrient Sensing Protein Kinases
Nutrients
Amino acids
TOR
Cell proliferation
Gene transcription
Protein synthesis
The mTOR Pathway
Current Treatments with mTOR Inhibitors
The everolimus combined with aromatase inhibitor improved progression‐free survival (10.6 vs 4.1 months) AND an increase in response rate (7% vs 0.4%).
Baselga, J. et al., 2012
*Current trials for glioblastoma, leukemia, sarcomas and colorectal, pancreatic, kidney, and lung cancers among others
In Breast Cancer, 50% of Tumors Harbor Somatic Mutations that Activate mTOR
Drug
Class
Study Populations
Common Toxicities
Everolimus
(RAD‐001)
Allosteric mToR inhibitor
Breast cancer
Fatigue, stomatitis, diarrhea, rash
Termsirolimus
Allosteric mTOR inhibitor
Breast cancer
Fatigue, stomatitis, diarrhea, rash
Ridaforolimus
Allosteric mTOR inhibitor
Breast cancer
Fatigue, stomatitis, anorexia, diarrhea, nausea
AZ02014
mTOR (TORC1/2) kinase inhibitor
Breast cancer
Fatigue, stomatitis, anorexia, diarrhea, nausea
XL76S
Dual PI3‐kinase/mTOR inhibitor
Breast cancer
Nausea, diarrhea, anorexia, rash elevated LFTS
BEZ235
Dual PI3‐kinase/mTOR inhibitor
Breast cancer
Fatigue, diarrhea, nausea, vomiting, anemia
GDC‐0980
Dual PI3‐kinase/mTOR inhibitor
Breast cancer
Nausea, fatigue, diarrhea
FDA approved for advanced cancers
Multiple and
Overlapping
Substrates
Why Might Protein Kinase Inhibitors/Activators Have Undesirable Side Effects??
Hundreds
Of Kinases
With Conserved
Catalytic Domain
Nutrient Sensing Protein Kinases
Nutrients
Amino acids
AMP levels
(low ATP)
TOR
AMPK
Cell proliferation
Gene transcription
Protein synthesis
⇑ATP production
⇓ATP utilization
AMPK Inhibits Growth & Promotes Energy Production
Hardie D G J Cell Sci 2004;117:5479-5487
Widespread Evidence That AMPK Activation Inhibits Cancer
Cancer
AMPK activation affect
Reference
Melanoma
Inhibits Invasion and metastasis
Cerezo M, 2013
Thyiroid cancer
Increased remission rates
Rusavy Z, 2013
Pancreatic cancer
Growth inhibition
Karnev E, 2013
Breast cancer
Increased survival
Aksoy S., 2013
Non‐small cell lung cancer (NSCLC)
Enhances radiation response
Strorozhuk, Y., 2013
Uterin Serous Carcinoma (USC)
Inhibits proliferation and migration
Sarfstein, R. 2013 Prostate Cancer
Reduced mortality
Bensimon L, 2013
Lymphoma
Inhibit proliferation
Rosilio C., 2013
Colorectal Cancer
Pro‐apoptotic
Cho, S., 2013
A Pro‐tumorigenic Role for AMPK
Jeon, S. and Hay, N., 2012
The AMPK Pathway and Cancer
Jeon, S. and Hay, N., 2012
PAS Kinase: A Nutrient Sensing Protein Kinase
AMP levels
(low ATP)
Nutrients
Mitochondial signals
Growth factors
Stress
Nutrients
(glucose)
kinase
AMPK
TOR
⇑ATP production
⇓ATP utilization
Cell proliferation
Gene transcription
Protein synthesis
PAS
Glucose
metabolism
PAS
PAS kinase:
kinase: an
an evolutionarily
evolutionarily conserved
conserved protein
protein kinase
kinase
PASK
PASK deletion:
deletion: protection
protection from
from HFD-induced
HFD-induced obesity
obesity
and
and liver
liver triglyceride
triglyceride accumulation
accumulation
Decreased weight gain
Hao et al, PNAS (2007)
PAS kinase‐defient mice protected from glucose intolerance and insulin resistance
Glucose tolerance
Insulin tolerance
Hao et al, PNAS (2007)
Mutations in hPASK Cause Hyperinsulin Secretion and are Associated with Maturity Onset Diabetes (MODY)
Semplici et al, 2012